a roadmap from design to commercialization: lifecycle implementation of the technology transfer...

A Roadmap from Design to Commercialization:

Lifecycle Implementation of the Technology Transfer Package

Brooks TaylorStaff Process Engineer & Site Tech Transfer Lead, bioMérieux, Inc.

Stephen M. PerryPresident & CEO, Kymanox

Tuesday, 10 March 2015

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Abstract• For technology transfer, having a proven roadmap for required

documentation is an essential success component. • Early adoption of detailed documentation for the product and

process helps facilitate communication, continuity, compliance and the ultimate goal – commercialization.

• As a technology transfer package evolves, it is able to tie into other critical areas such as process surveillance and continued process verification – and has many benefits to the organization that utilizes it.

• Based on real-world case studies, there are several best practices consistent with the 2nd Edition of ISPE’s Technology Transfer Good Practice Guide that have been proven to help key stakeholders.

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Agenda

• Introductions & Objectives• Background • Navigating the Roadmap• Summarizing the Solution• Q&A

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Introductions & ObjectivesBackground

Navigating the RoadmapSummarizing the Solution

Q&A

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“Bee” “Oh” “Marry” “You”

First things first…

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Mérieux Family

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Polling Activity

• Everyone, please stand up!• Please sit down if you…

– Are responsible for Tech Transfer at your organization.

– Have been a member of a Tech Transfer team in the last 12 months.

– Have (honestly) read the 2nd Edition GPG.

• The rest of you must be here to get CEUs

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Today’s Objectives• FOCUS

– Documentation of the Product and Process– And Evolution through Product Lifecycle– Especially New Products (Worst-Case)

• ANCILLARY– ICH Q8, Q9, & Q10– Technology Transfer Methodology– Technology Transfer Project Management– Continued Process Verification / Surveillance

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Q&A

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Background

• 2003 – ISPE 1st Edition: “Transfer Documentation” – Concept of a transfer package identified with very

little detail regarding the concept.

• 2005 – ICH Q8 (Development) and ICH Q9 (Risk Management)

• 2007 – ICH Q10 (Quality System)

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Background

• 2011 – FDA Process Validation Guidance

• 2014 – ISPE 2nd Edition: “Transfer Package” – Actually provides guidance on this solution with

more focus and organization on defining the documentation.

Lifecycle“Good project management and good archiving that capture scientific knowledge [is] more effective and

efficient.” [FDA, PV Guidance, 2011]16

1st Edition Reminder

“If at the end of a technology transfer exercise the Sending Unit and the Receiving Unit can demonstrate through clear documentation that: (1) the regulatory elements, and (2) the requisite business needs have been satisfied, then the technology transfer should be considered a success.”

[ISPE GPG for Technology Transfer, 1st edition]

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2nd Edition Solution

• Aligns with the concepts outlined in ICH guidance documents as well as the current FDA Process Validation Guidance.

• The 2nd Edition provides additional detail for more focus and organization on defining the documentation.

[ISPE GPG for Technology Transfer, 2nd edition]

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Key Definitions/Acronyms

• Technology Transfer Package (TTP)– The collection of all (including local and process-

related) knowledge required to run the process and analyze the product.

• Detailed Product and Process Description (DPPD)– The implementation of the TTP at bioMérieux in

Durham, NC.


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Key Definitions/Acronyms

• Sending Unit (START)– “The involved disciplines at an organization where

a designated product, process, or method is expected to be transferred from.”

• Receiving Unit (DESTINATION)– “The involved disciplines at an organization where

a designated product, process, or method is expected to be transferred and executed.”


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TTP…What is it, anyway?

• “A collection of all knowledge required to run the process and analyze the product.” (p. 12)

• “The technology transfer team should identify key information that needs to be collated, along with associated responsibilities, to help to ensure an effective knowledge transfer.” (p.12)


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TTP…What is it, anyway?

• Other key descriptors within 2nd edition:– Organized efficiently– Provide easy access to necessary information– Comprehensive


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TTP – Content Examples

• Knowledge Transfer Examples– Scientific and operational information– CQAs and material attributes– Process overview (especially CPPs)– Control Strategy – Continuous improvement ideas– Tacit (implicit) knowledge– HSE– Previous information from studies (PROs and CONs)– Others…

[ISPE GPG for Technology Transfer, 2nd edition]23

TTP – Content Examples

• Basic Requirements Examples– Business requirements– Product specific requirements (e.g., CQAs)– PFDs, unit operations, parameters, material attributes,

design space, trends, historical data, associated risks, CPPs– Facility capability assessment– Others…

[ISPE GPG for Technology Transfer, 2nd edition]24

Quote for PFDs:

“We recommend that firms diagram the process flow for the full-scale process. Process flow diagrams should describe each unit operation,

its placement in the overall process, monitoring and control points, and the component, as well as other processing material inputs (e.g.,

processing aids) and expected outputs (i.e., in-process materials and finished product). It is also useful to generate and preserve process

flow diagrams of the various scales as the process design progresses to facilitate comparison and decision making about their comparability.”

[FDA, PV Guidance, 2011]

FDA’s Thoughts

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Real-World Examples

• Enforcement – Warning Letters– 2001 – Eli Lilly (Parenteral)

• Failure to document and review the established manufacturing process described in the NDA filing.

– 2012 – Warner Chilcott Company (Oral)• “[Failure] to review relevant process design data

including process knowledge and understanding obtained during technical transfer activities in order to assure an overall understanding of the process impact on the quality attributes (e.g., assay) of your product.”

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More Reality• Enforcement – Warning Letters

– 2011 – Medela (Device)• “Failure to adequately establish and maintain a design

history file (DHF) for each type of device that contains or references the records necessary to demonstrate that the design was developed in accordance with the approved design plan.”

– 2011 – Hospira (Parenteral)• Failure to document method transfer.

Analytical Methods Like Mini Manufacturing Processes

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Q&A

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Phase Gates

• Initiation• Transfer• Commercialization• Evolution

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Phase Gates at bioMérieux, Inc.

TTP/DPPD Phase Gates

Product Development Phases Ph 0 & 1

Ph 2a Design

Ph 2bVerification

Ph 4 Commercialization

Ph 3Validation

Initiation Transfer Commercialization

Evolution

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Phase Gate Process

EvolutionPeriodic Review

Periodic ReviewPeriodic Review

2nd Location

CommercializationTransferInitiation

CommercializationTransferInitiation

Etc. Etc.

Periodic Review

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Phase Gate:Initiation

• Establish the minimum expectations up front in the Tech Transfer Project Plan or through a site SOP.

• TTP is a great tool for product development review.

• Provides a solution for a summary of the design freeze to be included in the regulatory review.

• “Where does transfer start?”

Initiation

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Phase Gate:Transfer

• Depending on the complexity of the transfer…

– CRO or other development facility Commercial location?

– Development facility Pilot line Commercial location?

– Initial commercial location New commercial location?

– Other scenarios (e.g., alignment with product development process (e.g., Ph 2a, Ph 2b, Ph 3))?

– Also consider analytical methods…small processes!

Transfer

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Phase Gate:Commercialization

• Commercialization (a.k.a., completion of transfer)– Final technology transfer project version is first

commercial version for the Receiving Unit.– It can simplify the regulatory review process when

compared to the Sending Unit version.– “When was the technology transfer complete?”– Establishes the first version for the evolution

(lifecycle) concept.

Commercialization

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Phase Gate:Evolution

• Evolution = lifecycle implementation– Design Space Knowledge Space.– Process changes due to technology (e.g.,

increased level of automation).– Increasing process robustness such as PAT

implementation.– Material supplier changes.– Scale-up.

Evolution

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DPPD = TTP

• Detailed Product and Process Description– A comprehensive technical summary that

describes the product, process, and test methods.– During the technology transfer process, the

Sending Unit provides initial product and process information to the Receiving Unit for the creation of the initial draft of the DPPD based upon that available product and process knowledge.

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Bi-Modal Distribution

“This makes sense”

“This is what we (want to) do”

“Why do all this stuff?”

“We just do it” 10

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To The 1s:

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“Collaborate.”

-R.J. Kirk

To The 0s:

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“Just Do It.”

- Phil Knight (Nike)

Getting the First DPPD• Management support

– Earlier-the-better

• People-driven– Over-the-wall– Push vs. pull– Mediated

– Dedicated Group (internal or 3rd party)

– Integrated Project Team Approach

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Over-the-Wall

Sender Receiver

DPPD

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Push-or-Pull Approach

Sender Receiver

DPPD

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MediatedSender Receiver Mediator

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Integrated Team Approach

PM

R&D Analytical I&E QC QA/RA Manufacturing

DPPD

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DPPD TOC

Sections Potential Content

Introduction

Describes the product and process included within the DPPD and indicates its current state (e.g., development, transfer, commercial manufacturing).

Source Document List

Lists the source documents and provides a reference for the documents used for the creation of DPPD.

Detailed Product Description

Provides a general description of the product(s) and a summary of the critical quality attributes.

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DPPD TOCSections Potential Content

Detailed Process Description

Visually describes the process through a summary process flowchart.

Describes the process in detail including processing area and conditions.

Provides a summary of major process steps for critical operations such as raw material dispensing, formulations, filling, and packaging.

Detailed Method Description

Describes test methods for raw materials, in-process intermediates, and product release required to support manufacturing.

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Process Flow Diagram (PFD)

Schematically represents the production process showing input and outputs of each unit operation. At a minimum, CPPs are included in the PFD. It is recommended to include other important process parameters in the PFD.

Equipment List Lists major equipment required for

production and indicates the associated Operations Unit as described on the PFD.

Materials List

Provides an itemized list of all materials required to manufacture the product with the corresponding quantity for the associated Operations Unit.

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Methods List

Lists test methods for raw materials, product release, and in-process testing according to the associated Operations Unit. Characterization methods are also identified, as needed.

Sampling List

Includes a list of samples according to the associated Operations Unit. The list may include sample description, test method, quantity, storage condition, and purpose, as applicable.

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Run History

Summarizes available data from manufacturing runs during the technology transfer process, such as pilot runs, technology transfer runs, and validation runs. The summary should include the associated protocol number, lot numbers, filling date, yield, and status of the run, at a minimum.

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Process Flow Diagrams

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Overview PFD

– Upstream Processing– Mid-Stream Processing– Downstream Processing– Final Finishing

Bulking 2

Filling

Filling

Filling

Degassing, Stoppering, and Capping

Autoclaving

Bulking 1

Warehousing

Packaging

Bottle Loading, Transport, and Orientation

Start of Manufacturing

Formulation

End of Manufacturing

Sensor / Bottle Assembly

Formulation/Filling 1

Headspace and Vacuum

Autoclaving

Warehouse

Packaging

Formulation

Inspection

#1 OVERVIEW

Chemweigh

Chemweigh

Loading

Details on Page 2, 3, and 6

Details on Page 4 and 6


Details on Page 6


Details on Page 7

Details on Page 7

Page 2

Page 2

Page 2

Page 3

Page 3

Page 3 and 6

Page 6Page 4

Page 6

Page 5

Page 5

Page 6

Page 7

Formulation/Filling 2

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Representative PFD

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PFD Best Practices• Visio

– Excel (Smart)– SuperPro Designer

• Include: CQAs, CPPs, IPCs/IPTs• Provide ranges

– 25 +/- 5 (SP & Tolerance)– 20 to 30 (NOTE: be careful with 20 – 30)

• Obey significant figures (X vs. X.XX)• Display Engineering Units

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More PFD Tips• Make hold steps easy to spot• Header/Footer (Pg X/Y, Ver. ID/Date, Owner, TTP)• Watermark: Draft, FIO, etc.• Flow top-to-bottom & left to right• Spatially accurate

– Show rooms

• Use COLOR– Don’t rely on color

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Knowledge Sources

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Source List• Elements of Initial Master Records (e.g., DMR)

– Bills of Materials (BOMs)– Raw Material Specifications– Product Specifications– Process Intermediate Specifications– Quality Control (QC) Test Procedures

• Process Flow Diagrams (PFDs)• Targeted Product Profile (TPP) (e.g., PRD)

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More Sources• Process Characterization Information and

Characterization Studies • Current Design History File (DHF)• Current Design and Development Plan (DDP)• Product and Process Risk Assessments• Development Reports• Package Inserts (Late Stage/Commercial)• Laboratory Notebooks (Earliest Stages)

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Or…• Existing DPPD

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Source List: Evolution• Existing DPPD• Batch Record / Manufacturing Changes• Equipment / SOP Changes• Material Changes

– Raw Materials– Consumables (e.g., container, label)

• Analytical Methods

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Equipment List• High Level Process / Unit Op. / PFD Op. (Pg #)• Equipment ID• Equipment Description• Status (New/Existing)• Supplier• Cleaning (N/A, Manual, CIP)• References• Comments

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Materials List• High Level Process / Unit Op. / PFD Op. (Pg #)• Part Number• Material Description• Quantity / UOM• Supplier / Catalog #• Storage Conditions• Specification References (Internal / External)• Comments

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Methods List• High Level Process / Unit Op. / PFD Op. (Pg #)• Applicable Raw Materials / Intermediates • Test Method Name / SOP • Development Status (e.g., ICH Q2 Validated) • Transfer Required (Yes / No) • Reference IDs (Internal / External)• Comments

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Sample List• High Level Process / Unit Op. / PFD Op. (Pg #)• Sample Material Description• Test Method(s) / Purpose (e.g., STAT)• Performed By (QC / Manufacturing / CLO) • # of Samples / Amount per Sample / Container• Storage Condition• Expiration / Test Window • Comments

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Run History• Product / Intermediate Description / Lot #• Run Type (R&D, Pilot, Validation, Commercial)• DOM / Release Date• Yield / Yield % / CQAs• Disposition• Comments

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Run History• Including FAILURESFAILURES, not just GOLDENGOLDEN batches• Evolution: Initial vs. Periodic Review

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Evolution through CPV

• Remember this about all process validation stages (I: Design, II: Qualification, III: CPV):

“Documentation is important so that knowledge gained about a product and process is accessible and

comprehensible to others involved in each stage of the lifecycle.”

[FDA, PV Guidance, 2011]

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Evolution through CPV

“Data gathered during this stage [Continued Process Verification] might suggest ways to improve and/or optimize the process by altering some aspect of the process or product, such as the operating conditions

(ranges and set-points), process controls, component, or in-process material characteristics.”

[FDA PV Guidance, 2011]

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Process Surveillance • TPP/DPPD provides one-stop shopping

– ID Stakeholders– URS– Data Roadmap– Prioritized Lists– Rationale – Automation / Software

User Requirements Specification

(URS)

Functional Requirements Specification

(FRS)

Detailed Design

Specification(DDS)

- Build System - Commissioning

DQ

PQ

OQ

IQ

Design Review

Timeline

Trace

abilit

y

Manag

emen

t

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• Regulatory guidance includes:“the perception of criticality as a continuum

rather than a binary state is more useful.” [FDA, PV Guidance, 2011]

• TTPs/DPPDs are a succinct, single source to summarize and document this continuum throughout the lifecycle.

Criticality as a Continuum

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Evolutionat bioMérieux, Inc. Durham

• Currently– 2 main production lines with approximately 20

products.

• Coming– New production line/facility.– New products in pipeline. – Demand for products increasing!

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Evolutionat bioMérieux, Inc., Durham

• Combined DPPDs according to similarities– Platform products

• Consistency for efficiency– Standardization across DPPDs for shared

processes, etc.

• DPPD updates are the responsibility of the product and process experts

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Challenges

• Initial implementation workload for approximately 20 products.

• “New expectation” from development for organizing information.

• Perception of “more documentation” in a documentation laden industry.

• Agreeing on the appropriate level of detail.

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Benefits: 1 of 2

• Single tool.• Training.

– Internal and External– Process flow– Core narrative description

• Audits.• Continued Process Verification / Surveillance.

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Benefits: 2 of 2

• Investigations• Alignment (e.g., between 2 manufacturing

locations)• Others

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Q&A

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The Solution

• Documentation of the Product and Process– TPP/DPPD Structure and Content

– It’s a family affair!

Process Flow Diagram

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The Solution• And Evolution through Product Lifecycle

– Phase Gates

– Initial Transfers vs. Periodic Review– Documents Continuum, CPV, Surveillance

• And…

Benefit$Benefit$

ChallengesChallenges

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Acknowledgements

• Will Darrigrand• Bill McNamara• Andy Gunn• Burak Ucar

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Q&A

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Contact Information

Stephen M. PerryKymanoxPresident & [email protected]: 847-239-2710

Brooks TaylorbioMérieux, Inc.Site Tech Transfer [email protected] Office: 919-620-5676

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mailto:[email protected]

mailto:[email protected]